Amino acid derivatives and anti-active oxygen agents

ABSTRACT

A novel anti-active oxygen agent which comprises as active ingredient an amino acid derivative represented by the following general formula (I): ##STR1## wherein Ar represents a 2-hydroxyphenyl, 2-hydroxy-1-naphthyl or pyridyl group, and one or more of the hydrogen atoms attached to the aromatic ring of these groups may be substituted with a halogen atom, or an alkyl, hydroxyl, hydroxyalkyl, nitro, alkoxyl or carboxyl group; R represents the side chain of an amino acid; X represents --CH 2  --NH-- or --CH═N--; Y represents a hydrogen atom, --COOR 1 , --SO 3  H, --CON(R 2 )R 3 , --CONHCH(R 5 )COOR 4  or --CH 2  OH (where each of R 1  to R 4  represents a hydrogen atom or an alkyl group, and R 5  represents the side chain of an amino acid); and n represents an integer of 0 or 1; 
     or its salt, 
     and which inhibits generation of active oxygen species, has a high safety and can be prepared at relatively low costs.

This application is the national phase of PCT/JP93/01842 filed on Dec. 20, 1993.

TECHNICAL FIELD

This invention relates to novel anti-active oxygen agents, and more specifically to anti-active oxygen agents which inhibit the generation of active oxygen and thus produce desired effects including preventive activities against skin-aging or other diseases.

BACKGROUND ART

In recent years, various disorders and diseases caused by active oxygen species such as superoxide anion radical (O₂ ⁻), hydroxyl radical (.OH), singlet oxygen (¹ O₂), and peroxide lipid have been reported. It is known that active oxygen species are deeply implicated as a cause in aging, canceration, pigmentation, inflammation or other skin disorders induced by the solar rays, particularly UV rays. The implication of active oxygen species in disorders and diseases in living bodies other than skin has also been explained. For example, active oxgen species derived from molecular oxygens added into ischemic tissues by blood reperfusion play an important role in ischemic reperfusion-induced disorders in organs such as heart, enteron, gaster, liver, kidney, and brain. Similarly, active oxygen species generated in living bodies bring about, for example, a wide variety of disorders and diseases such as inflammation, rheumatism, aging, cancer, arteriosclerosis, digestive diseases, kidney diseases, endocrine disorders, lung diseases, shock, disseminated intravascular coagulation syndrome, etc. It has been also reported that active oxygen species are responsible for denaturation and deterioration caused by oxidation of fats and oils in foods.

If the action of active oxygen species in such a wide range including living organs such as skin and foods could be inhibited, these disorders and diseases as well as denaturation and deterioration of foods would be prevented.

Known agents inhibiting the action of active oxygen species include enzyme-based anti-oxydants such as superoxide dismutase (SOD); non-enzyme-based anti-oxydants such as ascorbic acid, tocopherol and glutathione; and vegetable-derived anti-oxydant such as tannin. Recently, some attempts have been reported to inhibit the generation of active oxygen species by capture of metal ions, in view of the fact that metal ions present in living bodies function as catalyst in the generation of active oxygen species (For example, see "Free Radicals in Biology and Medicine", Oxford, Clarendon Press, p. 234, 1989).

Among known agents which inhibit the action of active oxygen species, SOD is limited in use because of its high costs and instability. Many of non-enzyme-based anti-oxydants such as ascorbic acid, tocopherol and glutathione are also instable and insufficient to inhibit the action of active oxygen species. Further, vegetable-derived anti-oxydants such as tannin often suffer from problems of stability, since they are susceptible to hydrolysis, oxydation, etc.

Desferrioxamines are typical compounds capable of capturing metal ions. However, they have so high metal ion capturing capacity for pharmaceutical use that they disturb the balance of metal ions in living bodies and thus invite side effects such as inflammation. Moreover, they have the disadvantage that they can not show sufficient inhibitory effects on the generation of active oxygen species by oral administration. Further, they are difficult to use in cosmetics and foods because of their high costs. Other than desferrioxamines, metal ion chelating agents such as 2,2'-dipyridyl, 1,10-phenanthrolene, and 2,2'-dipyridylamine were examined, but most of them showed toxicity or skin irritation.

An object of this invention is to provide a novel anti-active oxygen agent which inhibits the generation of active oxygen species, ensures a high safety and can be produced at relatively low costs.

DISCLOSURE OF THE INVENTION

This invention relates to an anti-active oxygen agent which comprises as an active ingredient an amino acid derivative represented by the following general formula (I): ##STR2## wherein Ar represents a 2-hydroxyphenyl, 2-hydroxy-1-naphthyl or pyridyl group, and one or more of the hydrogen atoms attached to the aromatic ring of these groups may be replaced by a halogen atom, or a C1-6 alkyl, hydroxyl, C1-6 hydroxyalkyl, nitro, C1-6 alkoxyl or carboxyl group, provided that when two or more of the hydrogen atoms are substituted, the substituents may be the same or different; R represents a side chain of an amino acid; X represents --CH₂ --NH-- or --CH═N--; Y represents a hydrogen atom, --COOR¹, --SO₃ H, --CON(R²)R³, --CONHCH(R⁵)COOR⁴ or --CH₂ OH (where each of R¹ to R⁴ represents a hydrogen atom or a C1-6 alkyl group, and R⁵ represents a side chain of an amino acid); and n represents an integer of 0 or 1;

or a salt thereof.

Among those represented by the general formula (I), the compounds represented by the following general formula (II) or (III) are novel and have never been described yet. ##STR3## wherein Ar¹ represents a 2-hydroxyphenyl group, and one or more of the hydrogen atoms attached to the aromatic ring of this group may similarly be substituted with a halogen atom, or an alkyl, hydroxyl, hydroxyalkyl, nitro, alkoxyl or carboxyl group as defined above in the general formula (I); R^(a) represents the side chain of valine, leucine, isoleucine, glutamic acid, glutamine, asparagine, arginine, lysine, methionine, threonine, tyrosine, tryptophan, homoserine or 3,4-dihydroxyphenylalanine, or a hydrogen atom; X¹ represents --CH₂ --NH--; and each of Y and n has the same meaning as defined above in the general formula (I). ##STR4## wherein Ar² represents a 2-hydroxy-1-naphthyl group, and one or more of the hydrogen atoms attached to the aromatic ring of this group may similarly be substituted with a halogen atom, or an alkyl, hydroxyl, hydroxyalkyl, nitro, alkoxyl or carboxyl group as defined above in the general formula (I); R^(b) represents the side chain of leucine, isoleucine, glutamic acid, glutamine, aspartic acid, asparagine, arginine, histidine, lysine, methionine, cysteine, serine, threonine, tyrosine, phenylalanine, tryptophan, homoserine or 3,4-dihydroxyphenylalanine; X² represents --CH═N--; and each of Y and n has the same meaning as defined above in the general formula (I).

In the general formula (I), Ar is preferably a 2-hydroxyphenyl, 2-hydroxy-5-chlorophenyl, 2-hydroxy-5-nitrophenyl, 2-hydroxy-1-naphthyl or 2-methyl-3-hydroxy-5-hydroxymethyl-4-pyridyl group in view of active oxygen inhibitory effects. The side chain (R) of an amino acid is preferably the side chain of histidine, serine, homoserine, tyrosine, 3,4-dihydroxyphenylalanine, glutamic acid, aspartic acid, lysine, threonine, glutamine, asparagine, arginine, phenylalanine, tryptophan, etc., also in view of the active oxygen inhibitory effects.

The compounds represented by the general formula (I) can be easily prepared, for example, according to the following scheme: ##STR5## wherein Ar, Y, R and n have the same meanings as defined above.

Compound (3) can be easily obtained by reacting a 2-hydroxy aromatic aldehyde (1) such as salicylaldehyde with an amino acid, an amino alcohol obtained by reducing an amino acid, amino acid ester or amino acid amide, these being collectively referred to as Compound (2), in the presence or absence of a solvent. Compound (4) can be derived by adding a hydrogenating agent such as sodium borohydride during or after the reaction between Compound (1) and Compound (2).

Though the anti-active oxygen compounds of the general formula (I) according to this invention may be directly administered to active oxygen generating systems, for example, intravenously, skin-topically, etc., they are usually incorporated in cosmetics such as lotion and cream; pharmaceuticals such as anti-inflammatory agent and antiarteriosclerotic agent; and foods such as edible oil. For use as the anti-skin aging component in cosmetics for example, they should be naturally comprised in an amount producing anti-skin aging activities, and may be comprised in an amount of, for example, 0.1 to 10% of the total weight of the cosmetics. For pharmaceutical use in human bodies, they should be naturally administered in an amount producing an intended effect, and may be administered in an amount of, for example, 0.1 to 1000 mg/day per adult. In order to prevent denaturation or deterioration of foods, they may be similarly added to the foods in an amount of 0.1 to 10% of the weight thereof. Otherwise, the anti-active oxygen compounds according to this invention may be formulated into special anti-skin aging preparations, e.g., in the form of ointment, instead of being incorporated in cosmetics.

BEST MODE FOR CARRING OUT THE INVENTION

This invention may be better understood by reference to the following examples including synthesis examples, test examples and use examples, which are not intended to limit the scope of the invention.

SYNTHESIS EXAMPLE 1

To 20 ml of a 2N aqueous solution of sodium hydroxide in which 5 g of L-histidine had been dissolved, 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were successively added. After stirring for 1 hour, additional 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were successively added. After stirring at room temperature for 1 hour, the unsolubles were filtered out and the filtrate was extracted with diethyl ether. The pH was adjusted to 6 with hydrochloric acid to give 8 g of N-(2-hydroxybenzyl)-L-histidine.

The measured results of the melting point, mass spectrum (FAB-MS) and NMR spectrum of the resulting compound are listed in Table 1 below.

SYNTHESIS EXAMPLES 2 TO 26

In the same way as described in Synthesis Example 1, the compounds shown in Table 1 were prepared. The measured results of the melting point, mass spectrum and NMR spectrum of each compound are also listed in Table 1.

                                      TABLE 1                                      __________________________________________________________________________     ArCH.sub.2NHCH(R.sub.15)(CH.sub.2).sub.nY                                      Syn                                                                            ex.                                                                               Ar            R.sub.15    n Y     m.p.                                                                               MS     NMR                            __________________________________________________________________________         ##STR6##                                                                                     ##STR7##   0 COOH  224˜ 225° C.                                                          m/z: 262(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 2.92(t, 2H), 3.42(t,                                                       1H), 3.60(dd, 2H),                                                             6.56(t, 1H), 6.68(d, 1H),                                                      6.88(s, 1H), 7.08(t, 1H),                                                      7.13(d, 1H), 7.59(s, 1H)       2                                                                                  ##STR8##                                                                                     ##STR9##   0 COOH  224˜ 226° C.                                                          m/z: 212(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 3.31(t, 1H), 3.71(dd,                                                      2H), 3.76(dd, 2H),                                                             6.60(t, 1H), 6.66(d, 1H),                                                      7.12(t, 1H), 7.19(d, 1H)       3                                                                                  ##STR10##                                                                                    ##STR11##  0 COOH  189˜ 190° C.                                                          m/z: 226(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 1.75˜1.97(m,                                                         2H), 3.31(t, 1H), 3.55(t,                                                      2H), 4.00(d, 2H), 6.80(t,                                                      1H), 6.87(d, 1H), 7.18(t,                                                      1H), 7.25(d, 1H)               4                                                                                  ##STR12##                                                                                    ##STR13##  0 COOH  251˜ 252° C.                                                          m/z: 288(M + H)                                                                       ((CD.sub.3).sub.2                                                              SO)δ(ppm): 2.89(m,                                                       2H), 3.34(t, 1H),                                                              3.73(dd, 2H), 6.68(d,                                                          2H), 6.76(dd, 2H),                                                             7.04(d, 2H), 7.05(t, 1H),                                                      7.13(t, 1H)                    5                                                                                  ##STR14##                                                                                    ##STR15##  0 COOH      m/z: 254(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 1.83(m, 2H), 2.18(t,                                                       2H), 3.12(t, 1H),                                                              3.58(dd, 2H), 6.56(t,                                                          1H), 6.60(d, 1H), 7.07(t,                                                      1H), 7.11(d, 1H)               6                                                                                  ##STR16##                                                                                    ##STR17##  0 COOH      m/z: 196(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 1.36(d, 3H), 3.33(q,                                                       1H), 3.72(dd, 2H),                                                             6.67(t, 1H), 6.73(d, 1H),                                                      7.20(t, 1H), 7.26(d, 1H)       7                                                                                  ##STR18##                                                                                    ##STR19##  0 COOH      m/z: 272(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 2.94(t, 2H), 3.43(t,                                                       1H), 3.60(dd, 2H),                                                             6.55(t, 1H), 6.61(d, 1H),                                                      7.04(d, 2H), 7.32(m, 4H)       8                                                                                  ##STR20##                                                                                    ##STR21##  0 COOH      m/z: 224(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 1.00(dd, 6H), 1.89(m,                                                      1H), 2.97(d, 1H),                                                              3.60(dd, 2H), 6.60(t,                                                          1H), 6.66(d, 1H), 7.10(t,                                                      1H), 7.18(d, 1H)               9                                                                                  ##STR22##                                                                                    ##STR23##  0 COOH      m/z: 182(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 3.19(s, 2H), 3.63(s,                                                       2H), 6.58(t, 1H), 6.62(d,                                                      1H), 7.10(t, 1H), 7.18(d,                                                      1H)                            10                                                                                 ##STR24##                                                                                    ##STR25##  0 COOH      m/z: 226(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 1.20(d, 3H), 3.05(d,                                                       1H), 3.62(dd, 2H),                                                             3.85(m, 1H), 6.58(t, 1H),                                                      6.64(d, 1H), 7.10(t, 1H),                                                      7.15(d, 1H)                    11                                                                                 ##STR26##                                                                                    ##STR27##  0 CONH.sub.2                                                                               m/z: 181(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 3.31(s, 2H), 3.67(s,                                                       2H), 6.59(t, 1H), 6.64(d,                                                      1H), 7.12(t, 1H), 7.20(d,                                                      1H)                            12                                                                                 ##STR28##                                                                                    ##STR29##  1 COOH      m/z: 196(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 2.47(t, 2H), 2.86(t,                                                       2H), 3.70(s, 2H), 6.65(t,                                                      1H), 6.70(d, 1H), 7.14(t,                                                      1H), 7.20(d, 1H)               13                                                                                 ##STR30##                                                                                    ##STR31##  1 SO.sub.3 H                                                                               m/z: 230(M - H)                                                                       (D.sub.2 O)δ(ppm):                                                       3.32(t, 2H), 3.50(t, 2H),                                                      .32(s, 2H), 7.05(m, 2H),                                                       7.41(m, 2H)                    14                                                                                 ##STR32##                                                                                    ##STR33##  0 H         m/z: 168(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 2.73(t, 2H), 3.67(s,                                                       2H), 3.70(s, 2H), 6.56(t,                                                      1H), 6.64(d, 1H), 7.12(t,                                                      1H), 7.18(d, 1H)               15                                                                                 ##STR34##                                                                                    ##STR35##  0 H         m/z: 218(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 2.78(tt, 4H), 3.63(s,                                                      2H), 6.52(t, 1H), 6.60(d,                                                      1H), 6.82(s, 1H), 7.07(t,                                                      1H), 7.14(d, 1H), 7.57(s,                                                      1H)                            16                                                                                 ##STR36##                                                                                    ##STR37##  0 COOH      m/z: 226(M + H)                       17                                                                                 ##STR38##                                                                                    ##STR39##  0 COOH             (D.sub.2 O+NaOD)δ(pp                                                     m): 1.29(d, 3H), 2.37(s,                                                       3H), 3.30(q, 1H),                                                              3.82(dd, 2H), 4.62(t,                                                          2H), 7.56(s, 1H)               18                                                                                 ##STR40##                                                                                    ##STR41##  0 COOH  221˜ 223° C.                                                          m/z: 301(M + H) (2Na )                                                                (D.sub.2 O)δ(ppm):                                                       2.49(s, 3H), 3.72(t, 1H),                                                      .00(dd, 2H), 4.45(dd,                                                          2H), 4.70(s, 2H), 7.62(s,                                                      1H)                            19                                                                                 ##STR42##                                                                                    ##STR43##  0 COOH      m/z: 271(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 1.21(d, 3H), 2.34(s,                                                       3H), 3.10(d, 1H),                                                              3.80(dd, 2H), 3.84(m,                                                          1H), 4.59(s, 2H), 7.53(s,                                                      1H)                            20                                                                                 ##STR44##                                                                                    ##STR45##  0 COOH      m/z: 285(M + H)                       21                                                                                 ##STR46##                                                                                    ##STR47##  0 COOH      m/z: 284(M + H)                       22                                                                                 ##STR48##                                                                                    ##STR49##  0 COOH      m/z: 307(M + H)                                                                       (D.sub.2 O)δ(ppm):                                                       2.51(s, 3H), 3.33(d, 2H),                                                      .88(t, 1H), 4.42(dd, 2H),                                                      .69(s, 2H), 7.30(s, 1H),                                                       7.68(s, 1H), 7.75(s, 1H)       23                                                                                 ##STR50##                                                                                    ##STR51##  0 CONH.sub.2                                                                               m/z: 306(M + H)                       24                                                                                 ##STR52##                                                                                    ##STR53##  0 COOH      m/z: 326(M + H)                       25                                                                                 ##STR54##                                                                                    ##STR55##  0 COOH      m/z: 317(M + H)                                                                       (D.sub.2 O+NaOD)δ(pp                                                     m): 2.28(s, 3H), 2.87(m,                                                       2H), 3.44(t, 1H),                                                              3.70(dd, 2H), 4.40(dd,                                                         2H), 7.20(d, 2H), 7.27(t,                                                      1H), 7.30(d, 2H) 7.43(s,                                                       1H)                            26                                                                                 ##STR56##                                                                                    ##STR57##  0 COOH      m/z: 333(M + H)                       __________________________________________________________________________

SYNTHESIS EXAMPLE 27

To 220 ml of absolute ethanol were added 1.6 g of L-histidine and 2.6 g of 2-hydroxy-1-naphthaldehyde, and the mixture was stirred for 5 days to give 2.4 g of N-(2-hydroxy-1-naphthal)-L-histidine.

The measured results of the melting point, mass spectrum and NMR spectrum of the resulting compound are listed in Table 2 below.

SYNTHESIS EXAMPLE 28 TO 67

In the same way as described in Synthesis Example 27, the compounds shown in Table 2 were prepared. The measured results of the melting point, mass spectrum and NMR spectrum of each compound are listed in Tables 2 and 3.

                                      TABLE 2                                      __________________________________________________________________________     ArCHNCH(R.sub.16)Y                                                             Syn.                                                                           ex.                                                                               Ar          R.sub.16      Y      m.p.                                                                               MS    NMR                              __________________________________________________________________________     27                                                                                 ##STR58##                                                                                  ##STR59##    COOH   171˜ 173° C.                                                          m/z: 310(M + H)                                                                      ((CD.sub.3).sub.2 SO)                                                          δ(ppm): 3.14(dd, 2H),                                                    4.69(t,1H), 6.71(d, 1H),                                                       6.86(s, 1H), 7.20(t, 1H),                                                      7.40(t, 1H), 7.62(s, 1H),                                                      7.64(d, 1H), 7.71(d, 1H),                                                      7.88(d, 1H), 8.85(s, 1H)         28                                                                                 ##STR60##                                                                                  ##STR61##    COOH   190˜ 191° C.                                                          m/z: 260(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 3.88(d, 2H), 4.51(t,                                                    1H), 6.82(d, 1H), 7.20(t,                                                      1H), 7.42(t, 1H), 7.63(d,                                                      1H), 7.73(d, 1H), 8.08(d,                                                      1H), 9.05(s, 1H)                 29                                                                                 ##STR62##                                                                                  ##STR63##    COOH   183˜ 184° C.                                                          m/z: 274(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.09(m, 2H),                                                            3.58(dt, 2H), 4,56(t, 1H),                                                     6.78(d, 1H), 7.24(t, 1H),                                                      7.45(t, 1H), 7.69(d, 1H),                                                      7.78(d, 1H), 8.08(d, 1H),                                                      9.11(s, 1H)                      30                                                                                 ##STR64##                                                                                  ##STR65##    COOH   187˜ 188° C.                                                          m/z: 272(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 0.96(d, 6H), 2.32(m,                                                    1H), 4.33(t, 1H), 6,78(d,                                                      1H), 7.22(t, 1H), 7.45(t,                                                      1H), 7.68(d, 1H), 7.79(d,                                                      1H), 8.08(d, 1H), 9.14(s,                                                      1H)                              31                                                                                 ##STR66##                                                                                  ##STR67##    COOH   156˜ 158° C.                                                          m/z: 336(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 3.07(d, 2H), 4.63(t,                                                    1H), 6.63(d, 2H), 6,75(d,                                                      1H), 7.02(d, 2H), 7.22(t,                                                      1H), 7.40(t, 1H), 7.65(d,                                                      1H), 7.76(d, 1H), 7.88(d,                                                      1H), 9.23(s, 1H)                 32                                                                                 ##STR68##                                                                                  ##STR69##    COOH   165˜ 166° C.                                                          m/z: 352(M + H)                                                                      ((CD.sub.3)SO)δ(ppm):                                                    .09(m, 2H), 4.60(t, 1H),                                                       6.46(d, 1H), 6.61(s, 1H),                                                      6.62(d, 1H), 6.74(d, 1H),                                                      7.21(t, 1H), 7.39(t, 1H),                                                      7.65(d, 1H), 7.75(d, 1H),                                                      7.89(d, 1H), 8.88(s, 1H)         33                                                                                 ##STR70##                                                                                  ##STR71##    CH.sub.2 OH                                                                           169˜ 170° C.                                                          m/z: 296(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.95(m, 2H), 3.63(m,                                                    1H), 3.97(d, 2H), 6.68(d,                                                      1H), 6.86(s, 1H), 7,15(t,                                                      1H), 7.41(t, 1H), 7.55(s,                                                      1H), 7.63(d, 1H), 7.69(d,                                                      1H), 7.95(d, 1H), 8.95(s,                                                      1H)                              34                                                                                 ##STR72##                                                                                  ##STR73##    COOH       m/z: 230(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 4.48(s, 2H), 6.74(d,                                                    1H), 7.20(t, 1H), 7.43(t,                                                      1H), 7.63(d, 1H), 7,74(d,                                                      1H), 8.01(d, 1H), 9.06(s,                                                      1H)                              35                                                                                 ##STR74##                                                                                  ##STR75##    CONH.sub.2 m/z: 229(M + H)                        36                                                                                 ##STR76##                                                                                  ##STR77##    COOH       m/z: 244(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 1.58(d, 3H), 4.56(q,                                                    1H), 6.79(d, 1H), 7.23(t,                                                      1H), 7.45(t, 1H), 7.67(d,                                                      1H), 7.77(d, 1H), 8.10(d,                                                      1H), 9.18(s, 1H)                 37                                                                                 ##STR78##                                                                                  ##STR79##    CH.sub.2 OH                                                                               m/z: 258(M + H)                        38                                                                                 ##STR80##                                                                                  ##STR81##    COOH       m/z: 286(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 0.97(d, 6H), 1.64(m,                                                    1H), 1.81(t, 2H), 4.48(t,                                                      1H), 6.79(d, 1H), 7.23(t,                                                      1H), 7.45(t, 1H), 7.67(d,                                                      1H), 7.77(d, 1H), 8.10(d,                                                      1H), 9.20(s, 1H)                 39                                                                                 ##STR82##                                                                                  ##STR83##    COOH       m/z: 286(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 0.96(t, 3H), 0.97(d,                                                    3H), 1.24(m, 1H), 1.51(m,                                                      1H), 2.08(m, 1H), 4.36(m,                                                      1H), 6.78(d, 1H), 7.21(t,                                                      1H), 7.44(t, 1H), 7.66(d,                                                      1H), 7.77(d, 1H), 8.08(d,                                                      1H), 9.14(s, 1H)                 40                                                                                 ##STR84##                                                                                  ##STR85##    COOCH.sub.3                                                                               m/z: 274(M + H)                        41                                                                                 ##STR86##                                                                                  ##STR87##    COOH       m/z: 274(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 1.17(d, 3H), 4.30(m,                                                    1H), 4.34(d, 1H), 6.70(d,                                                      1H), 7.19(t, 1H), 7.41(t,                                                      1H), 7.62(d, 1H), 7.72(d,                                                      1H), 7.99(d, 1H), 9.00(s,                                                      1H)                              42                                                                                 ##STR88##                                                                                  ##STR89##    COOH       m/z: 304(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.09(s, 3H), 2.20(m,                                                    2H), 2.55(t, 2H), 4.56(t,                                                      1H), 6.83(d, 1H), 7.27(t,                                                      1H), 7.48(t, 1H), 7.69(d,                                                      1H), 7.80(d, 1H), 8.12(d,                                                      1H), 9.21(s, 1H)                 43                                                                                 ##STR90##                                                                                  ##STR91##    COOH       m/z: 288(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.99(t, 2H), 4.70(t,                                                    1H), 6.78(d, 1H), 7.24(t,                                                      1H), 7.46(t, 1H), 7.68(d,                                                      1H), 7.77(d, 1H), 8.07(d,                                                      1H), 9.17(s, 1H)                 44                                                                                 ##STR92##                                                                                  ##STR93##    COOH       m/z: 287(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.83(t, 2H), 4.71(t,                                                    1H), 6.77(d, 1H), 7.23(t,                                                      1H), 7.45(t, 1H), 7.66(d,                                                      1H), 7.75(d, 1H), 8.04(d,                                                      1H), 9.10(s, 1H)                 45                                                                                 ##STR94##                                                                                  ##STR95##    COOCH.sub.3                                                                               m/z: 324(M + H)                        46                                                                                 ##STR96##                                                                                  ##STR97##    H          m/z: 266(M + H)                        47                                                                                 ##STR98##                                                                                  ##STR99##    COOH       m/z: 302(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.12(m, 1H), 2.29(m,                                                    1H), 2.33(t, 2H), 4.45(t,                                                      1H), 6.80(d, 1H), 7.25(t,                                                      1H), 7.45(t, 1H), 7.67(d,                                                      1H), 7.78(d, 1H), 8.09(d,                                                      1H), 9.17(s, 1H)                 48                                                                                 ##STR100##                                                                                 ##STR101##   COOH       m/z: 316(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.15(m, 1H), 2.29(m,                                                    1H), 2.43(t, 2H), 3.56(s,                                                      3H), 4.48(t, 1H), 6.85(d,                                                      1H), 7.26(t, 1H), 7.49(t,                                                      1H), 7.70(d, 1H), 7.82(d,                                                      1H), 8.11(d, 1H), 9.20(s,                                                      1H)                              49                                                                                 ##STR102##                                                                                 ##STR103##   COOCH.sub.3                                                                               m/z: 330(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.20(m, 1H), 2.30(m,                                                    1H), 2.43(t, 2H), 3.56(s,                                                      3H), 3.75(s, 3H), 4.57(t,                                                      1H), 6.90(d, 1H), 7.28(t,                                                      1H), 7.50(t, 1H), 7.73(d,                                                      1H), 7.83(d, 1H), 8.13(d,                                                      1H), 9.27(s, 1H)                 50                                                                                 ##STR104##                                                                                 ##STR105##   COOH       m/z: 317(M + H)                        51                                                                                 ##STR106##                                                                                 ##STR107##   COOH       m/z: 301(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.06(m, 1H), 2.18(t,                                                    2H), 2.25(m, 1H), 4.48(t,                                                      1H), 6.81(d, 1H), 7.23(t,                                                      1H), 7.46(t, 1H), 7.69(d,                                                      1H), 7.77(d, 1H), 8.10(d,                                                      1H), 9.16(s, 1H)                 52                                                                                 ##STR108##                                                                                 ##STR109##   COOH       m/z: 455(M + H)                        53                                                                                 ##STR110##                                                                                 ##STR111##   COOH       m/z: 329(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 1.57(d, 2H), 1.90(m,                                                    2H), 3.14(t, 2H), 4.15(t,                                                      1H), 6.64(d, 1H), 7.13(t,                                                      1H), 7.37(t, 1H), 7.56(d,                                                      1H), 7.63(d, 1H), 8.00(d,                                                      1H), 8.94(s, 1H)                 54                                                                                 ##STR112##                                                                                 ##STR113##   COOH       m/z: 320(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 3.20(d, 1H), 3.36(d,                                                    1H), 4.76(t, 1H), 6.79(d,                                                      1H), 7.22(m, 5H), 7.40(t,                                                      1H), 7.65(d, 1H), 7.75(d,                                                      1H), 7.89(d, 1H), 8.92(s,                                                      1H)                              55                                                                                 ##STR114##                                                                                 ##STR115##   COOH       m/z: 359(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 3.40(dd, 2H),                                                           4.77(t, 1H), 6.74(d, 1H),                                                      7.00(t, 1H), 7.09(t, 1H),                                                      7.16(s, 1H), 7.17(t, 1H),                                                      7.33(d, 1H), 7.34(t, 1H),                                                      7.62(dd, 2H), 7.72(dd, 2H),                                                    8.85(s, 1H)                      56                                                                                 ##STR116##                                                                                 ##STR117##   H          m/z: 315(M + H)                        57                                                                                 ##STR118##                                                                                 ##STR119##   COOH       m/z: 244(M + H)                        58                                                                                 ##STR120##                                                                                 ##STR121##   COOH       m/z: 288(M + H)                        59                                                                                 ##STR122##                                                                                 ##STR123##   COOH       m/z: 255(M + H)                        60                                                                                 ##STR124##                                                                                 ##STR125##   COOH   206˜ 209° C.                                                          m/z: 260(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 2.96(dd, 2H),                                                           4.31(t, 1H), 6.76(s, 1H),                                                      6.85(t, 1H), 6.87(d, 1H),                                                      7.33(t, 1H), 7.37(d, 1H),                                                      7.59(s, 1H), 8.32(s, 1H)         61                                                                                 ##STR126##                                                                                 ##STR127##   COOH       m/z: 294(M + H)                        62                                                                                 ##STR128##                                                                                 ##STR129##   COOH       m/z: 338(M + H)                        63                                                                                 ##STR130##                                                                                 ##STR131##   COOH       m/z: 290(M + H)                        64                                                                                 ##STR132##                                                                                 ##STR133##   COOH   148˜ 149° C.                                                          m/z: 256(M + H)                                                                      ((CD.sub.3).sub.2 SO)δ                                                   (ppm): 0.90(d, 6H), 2.28(m,                                                    1H), 3.88(d, 1H), 6.94(d,                                                      1H), 7.34(d, 1H), (s, 1H),                                                     8.54(s, 1H)                      __________________________________________________________________________

                                      TABLE 3                                      __________________________________________________________________________     Syn.                                                                           ex.                                                                               Structural formula      m.p.                                                                              MS     NMR                                       __________________________________________________________________________     65                                                                                 ##STR134##                m/z: 280(M + H)                                  66                                                                                 ##STR135##                m/z: 287(M + H)                                                                       ((CD.sub.3).sub.2 SO)δ(ppm):                                             3.85(d, 3H), 4.40(s, 2H), 6.77(d,                                              1H), 7.22(t, 1H), 7.44(t, 1H),                                                 7.66(d, 1H), 7.75(d, 1H), 8.07(d,                                              1H), 9.09(s, 1H)                          67                                                                                 ##STR136##                m/z: 449(M + H)                                  __________________________________________________________________________

SYNTHESIS EXAMPLE 68

To a 1N solution of sodium hydroxide in methanol (60 ml) were added L-histidine (4 g) and pyridoxal hydrochloride (5.5 g) and the mixture was stirred for 5 days to give N-pyridoxilidene-L-histidine-sodium salt (7 g).

The measured results of the melting point, mass spectrum and NMR spectrum of the resulting compound are listed in Table 4 below.

SYNTHESIS EXAMPLE 69 TO 72

In the same way as described in Synthesis Example 68, the compounds shown in Table 4 were prepared. The measured results of the melting point, mass spectrum and NMR spectrum of each compound are listed in Table 4.

                                      TABLE 4                                      __________________________________________________________________________     ArCHNCH(R.sub.17)COOH                                                          Syn                                                                            ex.                                                                               Ar            R.sub.17    m.p.                                                                               MS     NMR                                    __________________________________________________________________________     68                                                                                 ##STR137##                                                                                   ##STR138## 153˜ 155° C.                                                          m/z: 349(M + H) (as 2Na salt)                                                         (D.sub.2 O)δ(ppm): 2.30(s,                                               3H), 3.18(dd, 2H), 4.21(d, 1H),                                                4.70(s, 2H), 7.55(s, 1H), 7.57(s,                                              1H), 7.71(s, 1H), 7.78(s, 1H)          69                                                                                 ##STR139##                                                                                   ##STR140## 92˜ 95° C.                                                            m/z: 299(M + H) (as 2Na salt)                                                         (D.sub.2 O)δ(ppm): 2.43(s,                                               3H), 4.12(dd, 2H), 4.51(t, 1H),                                                4.88(s, 2H), 7.63(s, 1H), 8.98(s,                                              1H)                                    70                                                                                 ##STR141##                                                                                   ##STR142## 151˜ 153° C.                                                          m/z: 375(M + H) (as 2Na salt)                                                         (D.sub.2 O + NaOD)δ(ppm):                                                2.28(s, 3H), 2.72(m, 2H), 3.37(t,                                              1H), 4.89(s, 2H), 6.52(d, 2H),                                                 6.95(d, 2H), 7.42(s, 1H), 8.49(s,                                              1H)                                    71                                                                                 ##STR143##                                                                                   ##STR144## 162˜ 163° C.                                                          m/z: 411(M + H) (as 3K salt)                                                          (D.sub.2 O)δ(ppm): 2.06(m,                                               2H), 2.35(t, 2H), 2.39(s, 3H),                                                 4.29(t, 1H), 4.73(s, 2H), 7.55(s,                                              1H), 8.83(s, 1H)                       72                                                                                 ##STR145##                                                                                   ##STR146## 127˜ 129° C.                                                          m/z: 357(M + H) (as 2K salt)                                                          (D.sub.2 O)δ(ppm): 0.94(t,                                               3H), 1.00(d, 3H), 1.38(m, 2H),                                                 2.07(m, 1H), 2.39(s, 3H), 4.21(d,                                              1H), 4.72(d, 2H), 7.49(s, 1H),                                                 8.77(s, 1H)                            __________________________________________________________________________

TEST EXAMPLE 1 Test for Inhibitory Effects on UV-induced Lipid Peroxidation

The test was carried out on the basis of the methods described in Biochim. Biophys. Act., Vol. 1084, page 261, 1991 and Method in Enzymol., Vol. 52, page 302, 1978. Namely, 12 μl of an aqueous sodium hydroxide solution of each of the test compounds shown in Table 5 below was added to 1.2 ml of a homogenate of murine swiss 3T3 cells (i.e. a kind of murine skin cells) prepared by a conventional method in 20 mM phosphate buffer (protein content: 1.5 to 1.8 mg/ml). The final concentration of the test compounds was adjusted to be 1 mM and the pH of the solution was adjusted to 7.2 to 7.8. If test compounds were not soluble in an aqueous sodium hydroxide solution, they were dissolved in N,N-dimethyl sulfoxide (DMSO).

This solution (1.1 ml) was irradiated with UV rays (0.4 mW/cm², 90 min.) using a UVB lamp "EB-280C/J" (manufactured by Spectronics). To an aliquot (1.0 ml) of this solution were successively added 0.2 ml of an aqueous solution of sodium dodecyl sulfate and 1.0 ml of an aqueous solution of thiobarbituric acid/trichloroacetic acid/hydrochloric acid, and the mixed solution was heated in a boiling water bath for 15 minutes. After ice-cooling, the solution was extracted with 1.0 ml of 1-butanol to prepare a sample for determining peroxide lipid as absorbance at a wavelength of 535 nm using a spectrophotometer "Model 320" (manufactured by Hitachi).

The percent inhibition of lipid peroxidation of the test compounds was calculated from the following equation (1) and the results are shown in Table 5. ##EQU1## A₁ : Absorbance when a test compound was added. A₂ : Absorbance when a test compound was not added.

A₃ : Absorbance when a test compound was not added and UV rays were not irradiated.

                  TABLE 5                                                          ______________________________________                                         Test compounds           % Inhibition                                          ______________________________________                                         Example Compound of Synthesis Example 1                                                                     40                                                        Compound of Synthesis Example 2                                                                     59                                                        Compound of Synthesis Example 3                                                                     65                                                        Compound of Synthesis Example 4                                                                     60                                                        Compound of Synthesis Example 5                                                                     52                                                        Compound of Synthesis Example 6                                                                     66                                                        Compound of Synthesis Example 7                                                                     48                                                        Compound of Synthesis Example 8                                                                     60                                                        Compound of Synthesis Example 9                                                                     60                                                        Compound of Synthesis Example 10                                                                    56                                                        Compound of Synthesis Example 11                                                                    77                                                        Compound of Synthesis Example 12                                                                    29                                                        Compound of Synthesis Example 13                                                                    53                                                        Compound of Synthesis Example 14                                                                    45                                                        Compound of Synthesis Example 15                                                                    51                                                        Compound of Synthesis Example 28                                                                    20                                                Comp-   EDTA                 34                                                arative Citric acid          19                                                Example Vitamin C            -686                                              ______________________________________                                    

TEST EXAMPLE 2 Test for Inhibitory Effects on Hydroxyl Radical Formation (1)

The test was carried out in accordance with the method described in FEBS Letters, Vol. 128, page 347, 1981. Namely, to 1.1 ml of a solution of 54 mM sodium chloride in 9 mM phosphate buffer (hereinafter referred to as "PBS-I") were successively added 140 μl of a solution of each of the test compounds shown in Table 6 below in PBS-1, 5 μl of a 1 mM solution of ammonium iron (III) sulphate in hydrochloric acid, 140 μl of a solution of xanthine (manufactured by Tokyo Kasei Co.) in PBS-1, 14 μl a solution of deoxyribose (Sigma) in PBS-1 and xanthine oxidase (Sigma). The final concentrations of the test compounds, ammonium iron (III) sulphate, xanthine, deoxyribose and xanthine oxidase were adjusted to be 360 μM, 36 μM, 70 μM, 700 μM and 0.7 unit/ml, respectively. If test compounds were not soluble in PBS-1 alone, aqueous sodium hydroxide solution or DMSO was added. The pH of the solution was adjusted to 7.4 to 7.8.

After this solution was maintained at 37° C. for 15 minutes, 1 ml of an aqueous sodium hydroxide solution of thiobarbituric acid and 1 ml of acetic acid were successively added, and the mixed solution was heated in a boiling water bath for 10 minutes, then ice-cooled to prepare a sample for determining the hydroxyl radical at an excitation wavelength of 532 nm and a fluorescent wavelength of 553 nm using a fluorecent spectrophotometer "Model F-4000" (manufactured by Hitachi). The percent inhibition of the hydroxyl radical was calculated from the following equation (2) and the results are shown in Table 6. ##EQU2## F₁ : Intensity of fluorescence when a test compound was added. F₂ : Intensity of fluorescence when a test compound was added but deoxyribose was not added.

F₃ : Intensity of fluorescence when a test compound was not added.

F₄ : Intensity of fluorescence when neither test compound nor deoxyribose was added.

                  TABLE 6                                                          ______________________________________                                                 Test compounds   % Inhibition                                          ______________________________________                                         Example   Compound of Syn. Example 1                                                                        29                                                          Compound of Syn. Example 2                                                                        29                                                          Compound of Syn. Example 3                                                                        15                                                          Compound of Syn. Example 4                                                                        33                                                          Compound of Syn. Example 18                                                                       42                                                          Compound of Syn. Example 28                                                                       19                                                          Compound of Syn. Example 31                                                                       16                                                          Compound of Syn. Example 68                                                                       15                                                          Compound of Syn. Example 69                                                                       36                                                          Compound of Syn. Example 70                                                                       60                                                Comparative                                                                              EDTA               -121                                              Example   Citric acid        -33                                               ______________________________________                                    

TEST EXAMPLE 3 Test for Inhibitory Effects on Metal Ion-induced Lipid Peroxidation

The test was carried out according to the method described in Method in Enzymol., Vol. 52, page 302, 1978. A C57 black mouse was killed by cervical dislocation, and the whole brain extracted from the dissected head was washed with 20 mM phosphate buffer (hereinafter referred to as "PBS-2"). Then, the brain was added with PBS-2 in an amount of 19 times its wet weight, and the mixture was disrupted and homogenized with a homogenizer "Polytron" (manufactured by Kinematica). The thus prepared 5% solution of the murine brain homogenate in PBS-2 was diluted 1:5 with fresh PBS-2. To 800 μl of the resulting 1% solution of the murine brain homogenate in PBS-2 (protein content: 0.8 to 1.0 mg/ml) were successively added 100 μl of a PBS-2 solution of each of the test compounds shown in Table 7 below and 100 μl of an aqueous solution of ammonium iron (II) sulphate. The final concentration of the test compounds and ammonium iron (II) sulphate were adjusted to be 1 mM and 100 μM, respectively. If test compounds were not soluble in PBS-2 alone, an aqueous sodium hydroxide solution or DMSO was added. The pH of the solution was adjusted to 7.2 to 7.8.

The solution after heated at 37° C. for 30 minutes was added with 2.0 ml of an aqueous solution of thiobarbituric acid/trichloroacetic acid/hydrochloric acid, and the mixture was heated in a boiling water bath for 15 minutes. After ice-cooling, the solution was extracted with 1.0 ml of 1-butanol to prepare a sample for determining the peroxide lipid in the same way as described in Test Example 1.

The percent inhibition of lipid peroxidation of the test compounds was calculated from the following equation (3) and the results are shown in Table 7. ##EQU3## A₁ : Absorbance when a test compound was added. A₂ : Absorbance when a test compound was not added.

A₃ : Absorbance when a test compound was not added and heating at 37° C. for 30 minutes was not carried out.

                  TABLE 7                                                          ______________________________________                                                 Test compounds   % Inhibition                                          ______________________________________                                         Example   Compound of Syn. Example 1                                                                        26                                                          Compound of Syn. Example 2                                                                        41                                                          Compound of Syn. Example 3                                                                        21                                                          Compound of Syn. Example 4                                                                        26                                                          Compound of Syn. Example 18                                                                       26                                                          Compound of Syn. Example 27                                                                       87                                                          Compound of Syn. Example 28                                                                       80                                                          Compound of Syn. Example 29                                                                       78                                                          Compound of Syn. Example 30                                                                       43                                                          Compound of Syn. Example 31                                                                       90                                                          Compound of Syn. Example 32                                                                       83                                                          Compound of Syn. Example 33                                                                       95                                                          Compound of Syn. Example 34                                                                       57                                                          Compound of Syn. Example 35                                                                       16                                                          Compound of Syn. Example 36                                                                       80                                                          Compound of Syn. Example 37                                                                       30                                                          Compound of Syn. Example 38                                                                       74                                                          Compound of Syn. Example 39                                                                       50                                                          Compound of Syn. Example 40                                                                       88                                                          Compound of Syn. Example 41                                                                       79                                                          Compound of Syn. Example 42                                                                       86                                                          Compound of Syn. Example 43                                                                       40                                                          Compound of Syn. Example 44                                                                       90                                                          Compound of Syn. Example 45                                                                       85                                                          Compound of Syn. Example 46                                                                       80                                                          Compound of Syn. Example 47                                                                       90                                                          Compound of Syn. Example 48                                                                       85                                                          Compound of Syn. Example 49                                                                       81                                                          Compound of Syn. Example 50                                                                       85                                                          Compound of Syn. Example 51                                                                       84                                                          Compound of Syn. Example 52                                                                       100                                                         Compound of Syn. Example 53                                                                       96                                                          Compound of Syn. Example 54                                                                       83                                                          Compound of Syn. Example 55                                                                       87                                                          Compound of Syn. Example 56                                                                       57                                                          Compound of Syn. Example 57                                                                       44                                                          Compound of Syn. Example 58                                                                       40                                                          Compound of Syn. Example 59                                                                       11                                                          Compound of Syn. Example 60                                                                       34                                                          Compound of Syn. Example 61                                                                       45                                                          Compound of Syn. Example 62                                                                       45                                                          Compound of Syn. Example 63                                                                       60                                                          Compound of Syn. Example 64                                                                       60                                                          Compound of Syn. Example 65                                                                       73                                                          Compound of Syn. Example 66                                                                       20                                                          Compound of Syn. Example 67                                                                       38                                                          Compound of Syn. Example 68                                                                       15                                                          Compound of Syn. Example 69                                                                       23                                                          Compound of Syn. Example 70                                                                       27                                                          Compound of Syn. Example 71                                                                       13                                                          Compound of Syn. Example 72                                                                       14                                                Comparative                                                                              Citric acid        -15                                               Example   Vitamin C          -23                                                         Vitamin E          29                                                ______________________________________                                    

TEST EXAMPLE 4 Test for Inhibitory Effects on Lipid Peroxidation

To 900 μl of a 5% solution of the murine brain homogenate in PBS-2 prepared in the same way as described in Test Example 3 was added 100 μl of a PBS-2 solution of each of the test compounds shown in Table 8 below. The final concentration of the test compounds was adjusted to be 30 μM. If test compounds were not soluble in PBS-2 alone, an aqueous solution of sodium hydroxide or DMSO was added. The pH of the solution was adjusted to 7.2 to 7.8.

The solution after heated at 37° C. for 60 minutes was added with 1.0 ml of an aqeuous solution of thiobarbituric acid/trichloroacetic acid/hydrochloric acid, and the mixture was heated in a boiling water bath for 15 minutes. After ice-cooling, the solution was extracted with 2.0 ml of 1-butanol to prepare a sample for determining the lipid peroxide in the same way as described in Test Example 1. The percent inhibition of lipid peroxidation of the test compounds was calculated from the following equation (4), and the results are shown in Table 8. ##EQU4## A₄ : Absorbance when a test compound was added. A₅ : Absorbance when a test compound was not added.

A₆ : Abosrbance when a test compound was not added and heating at 37° C. for 90 minutes was not carried out.

                  TABLE 8                                                          ______________________________________                                                 Test compounds   % Inhibition                                          ______________________________________                                         Example   Compound of Syn. Example 1                                                                        53                                                          Compound of Syn. Example 2                                                                        26                                                          Compound of Syn. Example 16                                                                       89                                                          Compound of Syn. Example 17                                                                       56                                                          Compound of Syn. Example 18                                                                       44                                                          Compound of Syn. Example 19                                                                       59                                                          Compound of Syn. Example 20                                                                       91                                                          Compound of Syn. Example 21                                                                       90                                                          Compound of Syn. Example 22                                                                       91                                                          Compound of Syn. Example 23                                                                       39                                                          Compound of Syn. Example 24                                                                       85                                                          Compound of Syn. Example 25                                                                       55                                                          Compound of Syn. Example 26                                                                       39                                                          Compound of Syn. Example 27                                                                       98                                                          Compound of Syn. Example 28                                                                       70                                                          Compound of Syn. Example 69                                                                       15                                                          Compound of Syn. Example 71                                                                       29                                                Comparative                                                                              Citric acid        -13                                               Example   Vitamin C          -22                                                         Vitamin E          30                                                ______________________________________                                    

TEST EXAMPLE 5 Test for Inhibitory Effects on Hydroxyl Radical Formation (2)

To 75 μl of a solution of each of the test compounds shown in Table 9 below in 0.1M phosphate buffer (hereinafter referred to as "PBS-3") were successively added 75 μl of an aqueous solution of iron (II) sulphate, 20 μl of an aqueous solution of 5,5-dimethyl-1-pyrroline-N-oxide "DMPO" (manufactured by Dojin Chemical) and 75 μl of an aqueous solution of hydrogen peroxide. The final concentration of the test compounds, iron (II) sulphate, DMPO and hydrogen peroxide were adjusted to be 306 μM, 306 μM, 75 mM and 306 μM, respectively. If test compounds were not soluble in PBS-3 alone, an aqueous sodium hydroxide solution or N,N-dimethyl formamide was added.

This solution was subjected to determination for the hydroxy radical immediately (within 40 seconds), using an electron spin resonance (ESR) meter "JES-FR80S" (manufactured by Nippon Denshi).

The percent inhibition of hydroxy radicals was calculated from the equation (5), and the results are shown in Table 9. ##EQU5## E₁ : Signal magnitude when a test compound was added. E₂ : Signal magnitude when a test compound was not added.

                  TABLE 9                                                          ______________________________________                                                 Test compounds   % Inhibition                                          ______________________________________                                         Example   Compound of Syn. Example 1                                                                        27                                                          Compound of Syn. Example 2                                                                        44                                                          Compound of Syn. Example 3                                                                        45                                                          Compound of Syn. Example 4                                                                        27                                                          Compound of Syn. Example 16                                                                       56                                                          Compound of Syn. Example 18                                                                       43                                                          Compound of Syn. Example 22                                                                       51                                                          Compound of Syn. Example 27                                                                       71                                                          Compound of Syn. Example 28                                                                       56                                                          Compound of Syn. Example 29                                                                       60                                                          Compound of Syn. Example 30                                                                       25                                                          Compound of Syn. Example 47                                                                       32                                                          Compound of Syn. Example 48                                                                       54                                                          Compound of Syn. Example 52                                                                       43                                                          Compound of Syn. Example 53                                                                       68                                                          Compound of Syn. Example 60                                                                       33                                                          Compound of Syn. Example 68                                                                       10                                                          Compound of Syn. Example 69                                                                       19                                                          Compound of Syn. Example 70                                                                       28                                                          Compound of Syn. Example 71                                                                       21                                                Comparative                                                                              EDTA               -142                                              Example                                                                        ______________________________________                                    

TEST EXAMPLE 6 Test for UV Absorptive Activities

A solution of each of the test compounds shown in Table 10 below in ethanol was prepared for the final concentration to be 100 μM. If test compounds were not soluble in ethanol alone, water or DMSO was added.

The absorption spectrum of each sample was determined using a spectrophotometer "Model 320" (manufactured by Hitachi). The molar extinction coefficient in the both of UVA and UVB regions are shown in Table 10.

                  TABLE 10                                                         ______________________________________                                                                       Maximum                                                                        molar                                                            Wavelength (nm) of                                                                           extinction                                       Test compounds  maximum absorption                                                                           coefficient                                      ______________________________________                                         Example                                                                               Compound of  290           3,500                                               Syn. Example 18                                                                Compound of  290           5,300                                               Syn. Example 22                                                                Compound of  309           7,000                                               Syn. Example 27                                                                Compound of  307           10,000                                              Syn. Example 28                                                                Compound of  291           4,300                                               Syn. Example 68                                                                Compound of  336           3,000                                               Syn. Example 69                                                         ______________________________________                                    

This invention is further illustrated by the following use examples, in which the proportions of the components are expressed as % by weight.

USE EXAMPLE 1 (Skin cream)

Components 1 and 2 shown in Table 11 below were heated to 80° C. and 50° C., respectively, and the Component 2 was gradually added in portions to the Component 1 with stirring, to form an emulsion. Component 3 was added at 50° C. with stirring under water-cooling, and then the mixture was cooled to 35° C. to give a desired product.

The product where the compound of Synthetis Example 1 was incorporated was a highly skin-protective skin cream with anti-active oxygen property. This skin cream had gloss, high opacity and good feel on skin.

                  TABLE 11                                                         ______________________________________                                         Components                Proportion                                           ______________________________________                                         1   Squalane                  13.0                                                 Cetyl octanoate           13.0                                                 Di (cholesteryl, octyldodecyl)-N-lauroyl-L-                                                              5.0                                                  glutamic acid ester                                                            Compound of Synthesis Example 1                                                                          2.0                                                  Hardened oil              5.0                                                  Behenyl alcohol           1.0                                                  Stearic acid              2.0                                                  Self-emulsifiable glycerin monostearate                                                                  4.0                                                  Diglycerin oleate         1.0                                                  Dimethyl polysiloxane     0.3                                              2   Preservatives             0.2                                                  Sodium N-stearoyl-L-glutamate                                                                            0.4                                                  Xanthane gum              0.05                                                 1,3-Butylene glycol       7.0                                                  Purified water            45.85                                            3   Perfume                   0.2                                              ______________________________________                                    

USE EXAMPLE 2 (Skin milk)

Component 1 shown in Table 12 below was heated to 85° C. Component 2 was gradually added in portions to the Component 1 with stirring, and then Component 3 was added. The mixture was water-cooled to 30° C. with stirring to give a desired product.

This skin milk where the compound of Synthesis Example 1 was incorporated had a skin protective activity attributable to the anti-active oxygen property of the compound.

                  TABLE 12                                                         ______________________________________                                         Components              Proportion                                             ______________________________________                                         1      Squalane             13.0                                                      Compound of Synthesis Example 1                                                                     2.0                                                       Isocetyl octanoate   9.0                                                       Glycerin trioctanoate                                                                               4.0                                                       Propylene glycol stearate                                                                           0.5                                                       Behenyl alcohol      0.5                                                       Stearic acid         1.0                                                       Lipophilic glycerin monostearate                                                                    1.0                                                       Diglycerin oleate    0.5                                                       Polyethylene glycol stearate                                                                        2.5                                                2      Preservative         0.2                                                       Carboxyvinyl polymer 15.0                                                      (1.0% aqueous solution)                                                        Oleylphosphoric acid 0.4                                                       1,3-Butylene glycol  5.0                                                       Purified water       44.9                                               3      L-Arginine           0.3                                                       Purified water       0.2                                                ______________________________________                                    

USE EXAMPLE 3 (Lotion)

The components shown in Table 13 below were homogeneously dissolved to prepare a lotion.

This lotion where the compound of Synthesis Example 5 was incorporated had a skin-protective activity attributable to the anti-active oxygen property of the compound.

                  TABLE 13                                                         ______________________________________                                         Components            Proportion                                               ______________________________________                                         Methylparabin         0.2                                                      Sodium pyrrolidone-2-carboxylate                                                                     2.0                                                      1,3-Butylene glycol   5.0                                                      Compound of Synthesis Example 5                                                                      0.2                                                      Purified water        92.6                                                     ______________________________________                                    

INDUSTRIAL APPLICABILITY

As is evident from the above Examples, the anti-active oxygen agents according to this invention produce high inhibitory effects on the action of active oxygen species and can be easily prepared at low costs. They are physically and chemically stable. Accordingly, they can be used in anti-skin aging agents, cosmetics, pharmaceuticals or foods in order to prevent active oxygen species-induced disorders and diseases in human or other bodies as well as denaturation and deterioration of foods. Moreover, some of the anti-active oxygen compounds according to this invention have a UV absorptive power so that they are especially useful in cosmetics or the like. 

I claim:
 1. A method for inhibiting the generation of active oxygen species in a material, comprising applying an effective amount of an amino acid derivative represented by the following formula (I): ##STR147## wherein Ar represents a 2-hydroxy-1-naphthyl or pyridyl group, and one or more of the hydrogen atoms attached to the aromatic ring may be independently substituted with a halogen atom, or a C1-6 alkyl, hydroxy, C1-6 hydroxyalkyl, nitro, or C1-6 alkoxyl group; R represents the side chain of an amino acid; X represents --CH₂ --NH-- or --CH₂ ═NH--; Y represents a hydrogen atom, --COOR¹, --SO₃ H, --CON(R²)^(R) ³, --CONHCH(R⁵)COOR⁴ or --CH₂ OH (wherein each of R¹ to R⁴ represents a hydrogen atom or a C1-6 alkyl group, and R⁵ represents the side chain of an amino acid); and n represents an integer of 0 or 1;or its salt.
 2. The method of claim 1, wherein said Ar represents 2-methyl-3-hydroxy-5-hydroxymethyl-4-pyridyl group.
 3. The method of claim 1, wherein said X represents --CH₂ --NH--.
 4. The method of claim 1, wherein said Y represents --COOR¹.
 5. The method of claim 1, wherein said n represents integer of
 0. 6. A method for treatment against skin aging, comprising applying an effective amount of an amino acid derivative represented by the following formula (I): ##STR148## wherein Ar represents a 2-hydroxy-1-naphthyl or pyridyl group, and one or more of the hydrogen atoms attached to the aromatic ring may be independently substituted with a halogen atom, or a C1-6 alkyl, hydroxy, C1-5 hydroxyalkyl, nitro, or C1-6 alkoxyl group; R represents the side chain of an amino acid; X represents --CH₂ --NH-- or --CH₂ ═NH--; Y represents a hydrogen atom, --COOR¹, --SO₃ H, --CON(R²)R³, --CONHCH(R⁵)COOR⁴ or --CH₂ OH (wherein each of R¹ to R⁴ represents a hydrogen atom or a C1-6 alkyl group, and R⁵ represents the side chain of an amino acid); and n represents an integer of 0 or 1;or its salt.
 7. A method for inhibiting the generation of active oxygen species in a material, comprising applying an effective amount of an amino acid derivative represented by the following formula (I): ##STR149## wherein Ar represents a 2-hydroxyphenyl group, and one or more of the hydrogen atoms attached to the aromatic ring may be independently substituted with a halogen atom, or a C1-6 alkyl, hydroxy, C1-6 hydroxyalkyl, nitro, or C1-6 alkoxyl group; R represents the side chain of an amino acid; X represents --CH₂ --NH--; Y represents a hydrogen atom, --COOR¹, --SO₃ H, --CON(R²)R³, --CONHCH(R⁵)COOR⁴ or --CH₂ OH (wherein each of R¹ to R⁴ represents a hydrogen atom or a C1-6 alkyl group, and R⁵ represents the side chain of an amino acid); and n represents an integer of 0 or 1;or its salt.
 8. A method for inhibiting the generation of active oxygen species in a material, comprising applying an effective amount of an amino acid derivative represented by the following formula (I): ##STR150## wherein Ar represents a 2-hydroxyphenyl group, and one or more of the hydrogen atoms attached to the aromatic ring may be independently substituted with a halogen atom, or a C1-6 alkyl, hydroxy, C1-6 hydroxyalkyl, nitro, or C1-6 alkoxyl group; R represents the side chain of histidine, serine, homoserine, tyrosine, 3,4-dihydroxyphenylalanine, glutamic acid, aspartic acid, lysine, threonine, glutamine, asparagine, arginine, phenylalanine or tryptophan; X represents --CH═N--; Y represents a hydrogen atom, --COOR¹, --SO₃ H, --CON(R²)R³, --CONHCH(R⁵)COOR⁴ or --CH₂ OH (wherein each of R¹ to R⁴ represents a hydrogen atom or a C1-6 alkyl group, and R⁵ represents the side chain of an amino acid); and n represents an integer of 0 or 1;or its salt.
 9. The method of claim 6, wherein said Ar represents 2-methyl-3-hydroxy-5-hydroxymethyl-4-pyridyl group.
 10. The method of claim 6, wherein said X represents --CH₂ --NH--.
 11. The method of claim 6, wherein said Y represents --COOR¹.
 12. The method of claim 6, wherein said n represents integer of
 0. 13. A method for treatment against skin aging, comprising applying an effective amount of an amino acid derivative represented by the following formula (I): ##STR151## wherein Ar represents a 2-hydroxyphenyl group, and one or more of the hydrogen atoms attached to the aromatic ring may be independently substituted with a halogen atom, or a C1-6 alkyl, hydroxy, C1-6 hydroxyalkyl, nitro, or C1-6 alkoxyl group; R represents the side chain of an amino acid; X represents --CH₂ NH--; Y represents a hydrogen atom, --COOR¹, --SO₃ H, --CON(R²)R³, --CONHCH(R⁵)COOR⁴ or --CH₂ OH (wherein each of R¹ to R⁴ represents a hydrogen atom or a C1-6 alkyl group, and R⁵ represents the side chain of an amino acid); and n represents an integer of 0 or 1;or its salt.
 14. A method for treatment against skin aging, comprising applying an effective amount of an amino acid derivative represented by the following formula (I): ##STR152## wherein Ar represents a 2-hydroxyphenyl group, and one or more of the hydrogen atoms attached to the aromatic ring may be independently substituted with a halogen atom, or a C1-6 alkyl, hydroxy, C1-6 hydroxyalkyl, nitro, or C1-6 alkoxyl group; R represents the side chain of histidine, serine, homoserine, tyrosine, 3,4-dihydroxyphenylalanine, glutamic acid, aspartic acid, lysine, threonine, glutamine, asparagine, arginine, phenylalanine or tryptophan; X represents --CH═N--; Y represents a hydrogen atom, --COOR¹, --SO₃ H, --CON(R²)R³, --CONHCH(R⁵)COOR⁴ or --CH₂ OH (wherein each of R¹ to R⁴ represents a hydrogen atom or a C1-6 alkyl group, and R⁵ represents the side chain of an amino acid); and n represents an integer of 0 or 1;or its salt.
 15. An amino acid derivative represented by following general formula (II): ##STR153## wherein Ar¹ represents a 2-hydroxyphenyl group, and one or more of the hydrogen atoms attached to the aromatic ring may be independently substituted with a halogen atom, or an alkyl, hydroxy, hydroxyalkyl, nitro, or alkoxyl group; R^(a) represents the side chain of valine, leucine, isoleucine, glutamic acid, glutamine, asparagine, arginine, lysine, threonine, tyrosine, tryptophan, homoserine, 3,4-dihydroxyphenylalanine, or a hydrogen atom; X¹ represents -CH₂ --NH--; Y represents a hydrogen atom, --COOR¹, --SO₃ H, --CON(R²)R³ or --CONHCH(R⁵)COOR⁴ (wherein each of R¹ to R⁴ represents a hydrogen atom or a C1-6 alkyl group, and R⁵ represents the side chain of an amino acid); and n represents an integer of 0 or 1; or its salt.
 16. An amino acid derivative represented by following general formula (III): ##STR154## wherein Ar² represents a 2-hydroxy-1-naphthyl group, and one or more of the hydrogen atoms attached to the aromatic ring may be independently substituted with a halogen atom, or an alkyl, hydroxy, hydroxyalkyl, nitro, or alkoxyl group; R^(b) represents the side chain of glutamine, asparagine, histidine, cysteine, serine, threonine, tyrosine, tryptophan, homoserine, 3,4-dihydroxyphenylalanine, or a hydrogen atom; X² represents --CH═N--; Y represents a hydrogen atom, --COOR¹, --SO₃ H, or --CON(R²)R³, --CONHCH(R⁵)COOR⁴ or --CH₂ OH (wherein each of R¹ to R⁴ represents a hydrogen atom or a C1-6 alkyl group, and R⁵ represents the side chain of an amino acid); and n represents an integer of 0 or 1;or its salt.
 17. The amino acid derivative of claim 15, wherein said Ar¹ represents 2-hydroxyphenyl group.
 18. The amino acid derivative of claim 17, wherein said Y represents --COOH.
 19. The amino acid derivative of claim 17, wherein said n represents integer of
 0. 20. The amino acid derivative of claim 16, wherein said Ar² represents 2-hydroxy-1-naphthyl group.
 21. The amino acid derivative of claim 20, wherein said Y represents -COOR¹.
 22. The amino acid derivative of claim 20, wherein said n represents integer of
 0. 